Joint disease in rheumatoid arthritis (RA) is characterized by inflamed hyperplastic synovial tissue or ‘pannus’ formation (Firestein G. S., “Evolving Concepts of Rheumatoid Arthritis,” Nature 423:356-361 (2003)). Pannus is composed of various cell types that produce a vast array of inflammatory mediators, including cytokines and chemokines that destroy the extracellular matrix in the joint by direct and indirect mechanisms. Pannus is extremely vascular, providing portals of entry for effector cells to enter the joint from the circulation and mediate joint destruction via autocrine and paracrine mechanisms. As a result of neovascularization, inflammatory cell infiltration, and concomitant synovial cell hyperplasia, the volumes of the synovium and synovial fluid increase, resulting in joint swelling and pain (Maruotti et al., “Angiogenesis in Rheumatoid Arthritis,” Histol Histopathol 21:557-566 (2006)). Thus, inhibition of new blood vessel formation has been proposed as an important therapeutic approach for patients with inflammatory-erosive arthritis (De Bandt et al., “Blockade of Vascular Endothelial Growth Factor Receptor I (VEGF-RI), but not VEGF-RII, Suppresses Joint Destruction in the K/BxN Model of Rheumatoid Arthritis,” J Immunol 171:4853-4859 (2003)).
The lymphatic circulation has been known for many years to be an important secondary vascular system to remove fluid, macromolecules, and cells from the interstitial spaces, and it functions as a ‘compensatory’ system for blood circulation. However, studies of the lymphatic system have been hampered until recently by the lack of markers that definitively distinguish blood from lymphatic vessels and a paucity of knowledge about growth factors specific to lymphatic endothelial cells. Gene array analysis comparing lymphatic endothelial cells and blood vascular endothelial cells has recently identified numerous previously unknown lineage-specific markers for blood and lymphatic vascular endothelium. Newly identified lymphatic endothelium-specific markers include lymphatic endothelial hyaluronan receptor 1 (LYVE-1), prospero-related homeobox 1, vascular endothelial growth factor receptor 3 (VEGFR-3), and the mucin-type transmembrane glycoprotein podoplanin (Podgrabinska et al., “Molecular Characterization of Lymphatic Endothelial Cells,” Proc Natl Acad Sci USA 99:16069-16074 (2002); Kriehuber et al., “Isolation and Characterization of Dermal Lymphatic and Blood Endothelial Cells Reveal Stable and Functionally Specialized Cell Lineages,” J Exp Med 194:797-808 (2001); Mäkinen et al., “Isolated Lymphatic Endothelial Cells Transduce Growth, Survival and Migratory Signals via the VEGF-C/D Receptor VEGFR-3,” EMBO J 20:4762-4773 (2001); Hirakawa et al., “Identification of Vascular Lineage-Specific Genes by Transcriptional Profiling of Isolated Blood Vascular and Lymphatic Endothelial Cells,” Am J Pathol 162:575-586 (2003)).
The role of inflammation-induced lymphangiogenesis in the pathogenesis of joint disease and arthritis is unknown. Early clinical studies proposed that inflammation-driven lymphangiogenesis induces the expansion of the lymphatic network in an exacerbated manner such that the lymphatic vessels may be dysfunctional, as reported in psoriasis and Crohn disease (Braverman et al., “Microcirculation in Psoriatic Skin,” J Invest Dermatol 62:493-502 (1974); Ryan T J., “Microcirculation in Psoriasis: Blood Vessels, Lymphatics and Tissue Fluid,” Pharmacol Ther 10:27-64 (1980); Kovi et al., “Ultrastructure of Intestinal Lymphatics in Crohn's Disease,” Am J Clin Pathol 76:385-394 (1981), which are hereby incorporated by reference in their entirety). Recent studies have continued to focus on identifying and inhibiting signaling pathways that mediate lymphangiogenesis in several models of inflammation, including rheumatoid arthritis (see e.g. U.S. Patent Publication No. 20040120950 to Alitalo et al.). In general, however, the effects of manipulating lymphangiogenesis in these inflammatory conditions remain unclear. Therefore, a strategy for modulating the lymphatic system as a therapeutic approach for alleviating inflammation, particularly joint inflammation, is lacking.
The present invention is directed to overcoming this and other deficiencies in the art.